1. Field of the Invention
This invention relates to the use of a tissue-plasminogen activator variant for restoring function in dysfunctional hemodialysis catheters.
2. Description of Related Disclosures
Plasminogen activators are enzymes that cleave the peptide bond of plasminogen between amino acid residues 561 and 562, converting it to plasmin. Plasmin is an active serine proteinase that degrades various proteins, including fibrin.
Currently, five plasminogen activators are approved in the United States for treating coronary thromboses, but none are FDA-approved for catheter-directed thrombolysis. In the past three years, significant clinical research has been performed with use of recombinantly derived agents for catheter-directed therapy (CDT). Techniques have been refined and treatment of deep vein thrombosis (DVT) has been reported to be effective and safe with all available plasminogen activators in non-randomized, non-controlled observational studies (Elsharawy and Elzayat, Eur. J Vasc. Endovasc. Surg., 24: 209-214 (2002); Semba and Dake, Radiology, 191: 487-494 (1994); Chang et al., J. Vasc. Interv. Radiol., 12: 247-252 (2001); Castaneda et al., J. Vasc. Interv. Radial., 13: 577-580 (2002); Semba et al., Tech. Vasc. Interv. Radiol., 4: 99-106 (2001); Allie et al., Am. J. Cardiol., 90 (suppl 6A): 108H (2002)). See Verstraete, Am. J. Med., 109: 52-58 (2000) for an overview of third-generation thrombolytic drugs in general.
An early review of the literature suggested that the major complication rate undergoing thrombolysis with recombinant tissue-plasminogen activator (tPA) for peripheral arterial occlusive disease was 5.1% (Semba et al., J. Vasc. Interv. Radiol., 11: 149-161 (2000); Swischuk et al., J. Vasc. Interv. Radiol., 12: 423-430 (2001)). A tPA trial at a dose of 0.04 mg/kg/hr found major complications of 13% (Arepally et al., J. Vasc. Interv. Radiol., 13: 45-50 (2002)).
Initial results of reteplase in the treatment of acute lower extremity arterial occlusions showed a mortality rate of 6% with a currently employed low-dose regimen of 0.5 u/hour (Davidian et al., J. Vasc. Interv. Radiol., 11: 289-294 (2000)). More recently, a pilot study of reteplase employed for thrombolysis of deep venous thrombosis reported a major complication rate of 4% (Castaneda et al., supra).
Tenecteplase (TNK, TNKASE™, Genentech, Inc., South San Francisco, Calif.), a tissue-plasminogen activator, is a sterile, purified glycoprotein of 527 amino acids resulting from modifications of the complementary DNA for natural human tissue plasminogen activator. The modifications yielded a molecule with amino acid substitutions at three sites: the substitution of asparagine for threonine 103, the substitution of glutamine for asparagine 117, and a tetra-alanine substitution at amino acids 296-299 (lysine, histidine, arginine, and arginine). Tenecteplase is a serine protease that converts plasminogen to plasmin in the presence of fibrin, with limited conversion of plasminogen to plasmin in the absence of fibrin. Tenecteplase binds to fibrin in a thrombus and converts plasminogen to plasmin. This initiates local proteolysis of fibrin associated with the thrombus with limited proteolysis of systemic fibrinogen. Tenecteplase has the same mechanism of action as alteplase and has been shown to be potent and effective in promoting clot lysis in vitro (Refino et al., Thromb Haemost, 69(6):841 (1993); Keyt et al. Proc Natl Acad Sci. USA 91:3670-4 (1994).
In pre-clinical studies, tenecteplase has demonstrated increased potency, higher fibrin specificity, resistance to plasminogen activator inhibitor (PAI-1), and faster clot lysis, with less systemic fibrinolysis, plasminogenemia, and bleeding compared to alteplase (Refino et al., Thromb. Haemost., 70: 313-319 (1993); Keyt et al., supra; Collen et al., Thromb. Haemost., 72: 98-104 (1994); Patel et al., J. Vasc. Interv. Radiol., 12: 559-570 (2001)); Benedict et al., Circulation, 92: 3032-3040 (1995)).
In human clinical trials for treatment of acute myocardial infarction (AMI), tenecteplase demonstrated similar efficacy to alteplase, but major blood loss was reduced by 22%, need for blood transfusion was reduced by 23%, and minor bleeding decreased by 16% (Assessment of the Safety and Efficacy of a New Thrombolytic Investigators (ASSENT-2). Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double blind randomized trial. Lancet, 354: 716-722 (1999)). There was no significant difference in the rate of intracranial hemorrhage (0.9%). Subjects with an AMI within 6 hours of symptom onset were eligible for this study. The primary objective was to compare the mortality of subjects 30 days after treatment. Safety endpoints included rates of stroke, in-hospital myocardial reinfarction or pulmonary edema/cardiogenic shock, intracranial hemorrhage (ICH), major bleeding (defined as bleeding requiring blood transfusion or leading to hemodynamic compromise), and serious bleeding events. In the group of 16,949 subjects with AMI who were evaluated, there was no difference in the mortality rate at 30 days between tenecteplase and alteplase. In addition, there was no difference in ICH rate between tenecteplase- and alteplase-treated subjects (0.93% vs. 0.94%, respectively). However, there were significantly fewer non-cerebral major bleeding events in tenecteplase- versus alteplase-treated subjects (4.66% vs. 5.94%, respectively; p-value=0.0002), and fewer transfusions (4.25% vs. 5.49%, respectively; p=0.0002). Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria) were reported in <1% of subjects treated with tenecteplase. Anaphylaxis was reported in <0.1% of subjects treated with tenecteplase; however, causality was not established.
As a result of this study, tenecteplase is currently approved for use in the reduction of mortality associated with acute myocardial infarction (AMI) in weight-tiered doses ranging from 30 to 50 mg and given as a single intravenous bolus. Because of the superior safety profile seen in AMI and its increased clot lysis efficiency, investigators have been exploring the use of tenecteplase in non-coronary applications as an alternative thrombolytic agent (Semba et al., Tech. Vasc. Interv. Radiol., (2001), supra; Sze et al., J. Vasc. Interv. Radiol., 12: 1456-1457 (2001); Razavi et al., J. Vasc. Interv. Radiol., 13: (2), Part 2: S11 (February 2002); Nehme et al., J. Vasc. Interv. Radiol., 13: S109 (2002)).
Allie et al., Tenecteplase in Peripheral Thrombolysis: Initial Safety and Feasibility Experience, abstract 48 of Society of Interventional Radiology, March 2003 (page S17) discloses that continuous tenecteplase infusion (0.25 to 0.50 mg/hour) is a safe and feasible treatment for peripheral chemical thrombolysis. Further, tenecteplase diluted to a 0.0125 mg/ml solution was found to be a feasible treatment for thrombolysing occluded peripheral arteries and veins, with only moderate effect on fibrinogen levels (Burkart et al., J. Vasc. Interv. Radiol., 13: 1099-1102 (2002)), and when combined with eptifibatide, was found to be a feasible treatment for thrombolysing acute peripheral arterial and venous occlusions (Burkart et al., J. Vasc. Interv. Radiol., 14: 729-733 (2003)). Nehme et al., J. Vasc Intery Radiol, 13:S109 (2002) presented preliminary results of a study that evaluated the efficacy of tenecteplase in de-clotting 21 thrombosed arteriovenous polytetrafluoroethylene HD grafts in 14 subjects. Using a lyse-and-wait technique, tenecteplase at 2 mg and heparin at 3000 U were injected into the grafts via an angiocatheter. The duration of drug treatment was not published, but the authors stated that the mean procedural time was 65 minutes. Technical success, defined as complete graft recanalization, was 95% (20 of 21 grafts), and clinical success, defined as one successful HD after treatment, was 90% (19 of 21). Prior to additional mechanical thrombolysis, pulse was restored in 28% of the grafts (6 of 21). The authors reported one minor bleeding event at a previous graft puncture site.
Abbas et al. J. Amer. Coll. Cardiol., 46: 793-8 (2005) evaluated the safety and efficacy of intracoronary thrombolysis in 85 subjects with chronic total occlusion for >3 months and in whom a prior attempt at recanalization with percutaneous coronary intervention (PCI) was unsuccessful. Subjects received either a weight-adjusted dose (2-5 mg/hr) of alteplase (n=61) or a standard dose (0.5 mg/hr) of tenecteplase (n=24) for 8 hours, followed by PCI; the total dose was divided between the guide catheter and a 3-French intracoronary infusion catheter. Following intracoronary thrombolysis, recanalization was achieved in 54% of all subjects (both treatment groups combined) on repeat PCI. By multivariate analysis, lesion tapering and lack of bridging collaterals were the only predictors of success. Adverse events included hematoma (8% of all subjects) and bleeding requiring transfusion (3.5% of all subjects).
Tenecteplase is available in a commercially supplied 50-mg vial and approved for a single-bolus administration in patients with AMI (TNKASE™. Full prescribing information, 2002 Physicians Desk Reference, Thomas Medical Economics Co., Montvale, N.J.). When used in approved indications, tenecteplase is reconstituted in sterile water to achieve a final concentration of 5 mg/mL and administered intravenously as a single weight-adjusted bolus.
CATHFLO®ACTIVASE® (alteplase) is indicated for the restoration of function to central venous access (CVA) devices as assessed by the ability to withdraw blood. Approval was based on two pivotal Genentech-sponsored clinical trials of alteplase for the restoration of catheter function in adult and pediatric subjects over the age of two. Subsequently, a third trial in pediatric subjects (<17 years of age, including some <2 years of age) was performed. All three studies, whether placebo-controlled, double-blind or open-label trials, demonstrated that alteplase, when given at a dose of up to 2 mg/2 mL for up to two administrations, each followed by a dwell time of up to 120 minutes, is a safe and effective treatment for the restoration of catheter function in both adult and pediatric patients with occluded CVA catheters. Following administration of the first dose of alteplase, the rate of restoration of function to dysfunctional catheters after a dwell time of up to 120 minutes was 73.9%-76.5% for subjects ≧2 years of age and 69.1% for subjects <2 years of age. The rate of restoration of function following administration of up to two doses of alteplase was 83.5%-89.9% for subjects ≧2 years of age and 80.0% for subjects <2 years of age. A total of 39 of 1454 subjects (2.7%) reported serious adverse events during the three studies. All serious adverse events except three were judged to be unrelated to the alteplase. No ICHs, embolic events, or alteplase-related major bleeding were reported during the trials. The most common serious adverse event in these trials was sepsis/bacteremia (18%).
For peripheral catheter-directed thrombolytic therapy, lyophilized tenecteplase is reconstituted in sterile water (5 mg/mL) and further diluted in normal saline (0.01 to 0.25 mg/mL) (Semba et al., Tech. Vasc. Interv. Radiol., supra, (2001); Allie et al., Am. J. Cardiol., supra); Razavi et al., supra; Semba et al., J. Vasc. Interv. Radiol., 13: (2), Part 2: S75 (February 2002). Specifically, Razavi et al., supra, reports that using a 0.01 mg/mL dilution of tenecteplase in normal saline infused at 25 to 50 mL/hr (0.25-0.5 mg/hr) results in angiographic efficacy in arterial and venous clot lysis (Razavi et al., supra). Additionally, Razavi et al., J. Endovasc. Ther., 9:593-598 (2002) disclose that such doses of tenecteplase are safe and effective in peripheral catheter-directed thrombolytic therapy of arterial occlusions and deep vein thrombosis.
According to the United States Renal Data System, there were over 440,000 persons in the United States with end-stage renal disease at the end of 2003 (National Institutes of Health, U.S. Renal Data System. USRDS 2005 annual data report: atlas of end-stage renal disease in the United States. Bethesda (Md.): National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (2005)). Of these, the vast majority underwent regular hemodialysis (HD), generally three times per week. Many of these patients receive HD through tunneled central venous catheters. For these patients, low catheter flow rates due to thrombotic obstruction of the lumens remain a frequent complication and have been estimated to affect 3%-10% of all HD sessions and 87% of all catheters at some time prior to their removal (Moss et al., Am J Kidney Dis; 12:492-8 (1988); Gibson and Mosquera, Nephrol Dial Transplant 1991;6:269-74 (1991); Suhocki et al., Am J Kidney Dis, 28:379-86 (1996)).
The Kidney Dialysis Outcome Quality Initiative (KDOQI) Clinical Practice Guidelines for Vascular Access defines HD catheter dysfunction as the “failure to attain and maintain an extracorporeal blood flow (≧300 mL/min) sufficient to perform HD without significantly lengthening HD treatment” (National Kidney Foundation, K/DOQI clinical practice guidelines for vascular access: updated 2000. Am J Kidney Dis 37:S137-81 (2001)). The KDOQI guidelines for managing failing catheters recommend the use of thrombolytics as first-line therapy.
The use of alteplase as an intra-luminal dwell to treat HD catheter dysfunction has been reported, for example, in Daeihagh et al. Am J Kidney Dis 36:75-9 (2000); Habowski et al., J Am Soc Nephrol 11:185A (2000); O'Mara et al., J Am Soc Nephrol., 11:292A (2000); Roberts et al., J Am Soc Nephrol 11:195A (2000); Zacharias et al., Ann Pharmacother., 27-33 (2000); Hammes et al., J Am Soc Nephol 12:290A (2001); Spry and Miller, Dial Transplant 30:10-2 (2001); Cairoli O. Practical application: using t-PA (Cathflo™ Activase®) overnight in catheter clearance on tunnel catheters used for hemodialysis. Proceedings of the 22nd Annual Conference on Dialysis; Tampa (Fla.) (Mar. 4-6, 2002); Eyrich et al. Am J Health Syst Pharm 59:1437-40 (2002); Little and Walshe Am J Kidney Dis 39:86-91 (2002); and Dowling et al., Nephrol Nurs J; 31:199-200 (2004). Alteplase doses of 1 to 2 mg were given in varying volumes, with dwell times ranging from 20 minutes to 96 hours. Most of these studies have small numbers of patients, use different dosing regimens, have little safety information, and have varied definitions of efficacy. Thus, no thrombolytic has been studied in randomized, well-controlled clinical trials or been approved by the U.S. Food and Drug Administration (FDA) for treatment of occluded HD catheters.
U.S. patent application Ser. No. 10/697,142 filed 30 Oct. 2003 discloses using diluted solutions of tenecteplase to treat pathological collections of fibrin-rich fluids, for example, the fluids found to obstruct catheters, including HD catheters.
There is a need for using a fibrin-specific plasminogen activator efficaciously and uniformly to clear out HD catheters containing pathological collections of fluid. For example, there is a need for HD catheter-directed thrombolysis in a clinical setting that allows higher doses of tenecteplase than set forth in U.S. patent application Ser. No. 10/697,142 filed 30 Oct. 2003. Specifically, there is a need to administer a fibrin-specific plasminogen activator locally into the HD catheter lumen without systemic exposure to provide a way to salvage catheters with suboptimal flow rates while minimizing the risk of adverse events associated with systemic use of such agent. Because of the time constraints of HD sessions, there is a need for an agent such as tenecteplase, with high potency, high fibrin specificity, and efficiency to rapidly lyse clots. Furthermore, a continuing need exists for the prevention and removal of fibrin from such HD devices, as certain bacteria have binding sites that favor sticking to fibrin, in particular.